Darell Bigner

Overview:

The Causes, Mechanisms of Transformation and Altered Growth Control and New Therapy for Primary and Metastatic Tumors of the Central Nervous System (CNS).

There are over 16,000 deaths in the United States each year from primary brain tumors such as malignant gliomas and medulloblastomas, and metastatic tumors to the CNS and its covering from systemic tumors such as carcinoma of the lung, breast, colon, and melanoma. An estimated 80,000 cases of primary brain tumors were expected to be diagnosed last year. Of that number, approximately 4,600 diagnosed will be children less than 19 years of age. During the last 20 years, however, there has been a significant increase in survival rates for those with primary malignant brain tumors.

For the last 44 years my research has involved the investigation of the causes, mechanism of transformation and altered growth control, and development of new methods of therapy for primary brain tumors and those metastasizing to the CNS and its coverings. In collaboration with my colleagues in the Preston Robert Tisch Brain Tumor Center, new drugs and those not previously thought to be active against CNS tumors have been identified. Overcoming mechanisms of drug resistance in primary brain tumors are also being pursued.

As the founding Director of the Preston Robert Tisch Brain Tumor Center, I help coordinate the research activities of all 37 faculty members in the Brain Tumor Center. These faculty members have projects ranging from very basic research into molecular etiology, molecular epidemiology, signal transduction; translational research performing pre-clinical evaluation of new therapies, and many clinical investigative efforts. I can describe any of the Brain Tumor Center faculty member’s research to third year students and then direct them to specific faculty members with whom the students would like a discussion.

We have identified through genome-wide screening methodology several new target molecules selectively expressed on malignant brain tumors, but not on normal brain. These include EGFRwt, EGFRvIII, and two lacto series gangliosides, 3'-isoLM1 and 3',6'-isoLD1 and chondroitin proteoglycan sulfate. We raised conventional and fully human monoclonal antibodies against most of these targets as well as having developed single fragment chain molecules from naïve human libraries.

My personal research focuses on molecularly targeted therapies of primary and metastatic CNS tumors with monoclonal antibodies and their fragments. Our study we conducted was with a molecule we discovered many years ago, the extracellular matrix molecule, Tenascin. We have treated over 150 malignant brain tumor patients with excellent results with a radiolabeled antibody we developed against Tenascin. We are collaborating with Dr. Ira Pastan at NIH to develop tumor-targeted therapies by fusing single fragment chain molecules from monoclonal antibodies or from naïve human libraries to the truncated fragment of pseudomonas exotoxin A. One example of this is the pseudomonas exotoxin conjugated to a single fragment chain antibody that reacts with wild type EGFR and EGFRvIII, two overexpressed proteins on glioblastoma. The immunotoxin, called D2C7-IT, is currently being investigated in an FDA dose-escalation study, in which patients undergoing treatment of this investigational new drug are showing positive responses. My laboratory is also working with Matthias Gromeier, creator of the oncolytic poliovirus - a re-engineered poliovirus that is lethal to cancer cells, but not lethal to normal cells. The oncolytic poliovirus therapeutic approach has shown such promising results in patients with glioblastoma, that it was recently featured on a on a special two-segment program of 60 Minutes. The next clinical step will be to combine both the virus and the immunotoxin with anti-PD1, an immune checkpoint blockade inhibitor. We believe that regional tumor-targeted cytotoxic therapies, such as oncolytic poliovirus and the D2C7 immunotoxin, not only specifically target and destroy tumor cells, but in the process, initiate immune events that promote an in situ vaccine effect. That immune response can be amplified by human checkpoint blockade to engender a long-term systemic immune response that effectively eliminates recurrent and disseminated GBM cells. Ultimately, all three agents may be used together, providing different antigenic targets and cytotoxicity mechanisms.

We have identified through genome-wide screening methodology several new target molecules selectively expressed on malignant brain tumors, but not on normal brain. These include glycoprotein non-metastatic B (GPNMB), a molecule shared with malignant melanoma; MRP3, a member of the multidrug resistant family; and two lacto series gangliosides, 3'-isoLM1 and 3',6'-isoLD1 and chondroitin proteoglycan sulfate. We are raising conventional monoclonal antibodies against all of these targets as well as developing single fragment chain molecules from naïve human libraries. When necessary, affinity maturation in vitro is carried out and the antibodies and fragments are armed either with radioactive iodine, radioactive lutetium, or radioactive Astatine-211. Other constructs are evaluated for unarmed activity and some are armed with Pseudomonas exotoxin. After development of the constructs, they are evaluated in human malignant glioma xenograft systems and then all studies necessary for Investigational New Drug Permits from the Food and Drug Administration are carried out prior to actual clinical trial.

I was senior author on a New England Journal of Medicine paper that was the first to show markedly increased survival in low to intermediate grade gliomas with an isocitrate dehydrogenase mutation.

The first fully funded Specialized Research Center on Primary and Metastatic Tumors to the CNS funded by the National Institutes of Health, of which I am Principal Investigator, is currently in its 27th year of continuous funding. My NCI MERIT Award, which ranked in the upper 1.2 percentile of all NIH grants at the time of its last review, is currently in its 40th year of continuous funding. It is one of the few MERIT awards awarded three consecutive times, and it is the longest continually funded grant of the NCI Division of Cancer Diagnosis and Treatment.

In addition to the representative publications listed, I have made national presentations and international presentations during the past year.

My laboratory has trained over 50 third year medical students, residents, Ph.D. students, and postdoctoral fellows and I have a great deal of experience in career development with some students having advanced all the way from fellowship status to endowed professorships. A major goal with third year medical students is to perform work that can be presented in abstract form at national or international meetings and to obtain publication in major peer-reviewed journals.

Positions:

E. L. and Lucille F. Jones Cancer Research Professor, in the School of Medicine

Neurosurgery
School of Medicine

Professor of Neurosurgery

Neurosurgery
School of Medicine

Chief, Division of Experimental Pathology

Pathology
School of Medicine

Professor of Surgery

Surgery
School of Medicine

Professor of Pathology

Pathology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

M.D. 1965

Duke University

Ph.D. 1971

Duke University

Intern, Surgery

Duke University

Fellow, Neurological Surgery

Duke University

Clinical Associate, Medical Neurology

National Institutes of Health

Grants:

Innate Antiviral Signals for Cancer Immunotherapy

Administered By
Neurosurgery
Awarded By
National Institutes of Health
Role
Co-Principal Investigator
Start Date
End Date

Cancer Immunotherapy Through Intratumoral Activation of Recall Responses

Administered By
Neurosurgery
Awarded By
National Institutes of Health
Role
Co-Sponsor
Start Date
End Date

Anti-tumor efficacy of EGFR-targeting immunotoxin in combination with CCNU or PD-L1 blockade in glioma mouse models

Administered By
Neurosurgery, Neuro-Oncology
Role
Principal Investigator
Start Date
End Date

Vaccine Immunotoxin and Radioimmunotherapy of Primary and Metastatic CNS Tumors

Administered By
Pathology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

A Genetically Modified Poliovirus and Immunotoxin for Malignant Brain Tumors

Administered By
Neurosurgery, Neuro-Oncology Clinical Research
Role
Investigator
Start Date
End Date

Publications:

MGMT: Immunohistochemical Detection in High-Grade Astrocytomas.

Glioma therapeutic resistance to alkylating chemotherapy is mediated via O6-methylguanine-DNA methyltransferase (MGMT). We hypothesized that a CD45/HAM56/MGMT double-stained cocktail would improve MGMT discrimination in tumor cells versus inflammatory and endothelial cells (IEC). Total MGMT protein was quantified by IHC on 982 glioblastomas (GBM) and 199 anaplastic astrocytomas. Correcting for IEC was done by a CD45/HAM56/MGMT 2-color cocktail. Lowest IEC infiltrates (IEC "cold spots") were identified to quantitate MGMT as well as the percentage of IEC% in the IEC cold spots. MGMT promoter methylation (PM) was also determined. Among the GBM biopsies, mean uncorrected and corrected MGMT% were 19.87 (range 0-90) and 16.67; mean IEC% was 18.65 (range 1-80). Four hundred and fifty one (45.9%) GBM biopsies were positive MGMT PM. Both uncorrected and corrected MGMT% positivity correlated with PM. All 3 MGMT scores correlated with overall survival (OS) in GBM's. Cold spot IEC% was also positively associated with OS. These effects remained in a multivariate model after adjusting for age and disease status. Prognosis determined by correcting MGMT% score for IEC% is not improved in this analysis. However, IEC COLD SPOT score does provide additional prognostic information that can be gained from this correction method.
Authors
Lipp, ES; Healy, P; Austin, A; Clark, A; Dalton, T; Perkinson, K; Herndon, JE; Friedman, HS; Friedman, AH; Bigner, DD; McLendon, RE
MLA Citation
Lipp, Eric S., et al. “MGMT: Immunohistochemical Detection in High-Grade Astrocytomas..” J Neuropathol Exp Neurol, vol. 78, no. 1, Jan. 2019, pp. 57–64. Pubmed, doi:10.1093/jnen/nly110.
URI
https://scholars.duke.edu/individual/pub1361677
PMID
30500933
Source
pubmed
Published In
J Neuropathol Exp Neurol
Volume
78
Published Date
Start Page
57
End Page
64
DOI
10.1093/jnen/nly110

Mutant allele quantification reveals a genetic basis for TP53 mutation-driven castration resistance in prostate cancer cells.

The concept that human cancer is in essence a genetic disease driven by gene mutations has been well established, yet its utilization in functional studies of cancer genes has not been fully explored. Here, we describe a simple genetics-based approach that can quickly and sensitively reveal the effect of the alteration of a gene of interest on the fate of its host cells within a heterogeneous population, essentially monitoring the genetic selection that is associated with and powers the tumorigenesis. Using this approach, we discovered that loss-of-function of TP53 can promote the development of resistance of castration in prostate cancer cells via both transiently potentiating androgen-independent cell growth and facilitating the occurrence of genome instability. The study thus reveals a novel genetic basis underlying the development of castration resistance in prostate cancer cells and provides a facile genetic approach for studying a cancer gene of interest in versatile experimental conditions.
Authors
Lei, K; Sun, R; Chen, LH; Diplas, BH; Moure, CJ; Wang, W; Hansen, LJ; Tao, Y; Chen, X; Chen, C-PJ; Greer, PK; Zhao, F; Yan, H; Bigner, DD; Huang, J; He, Y
MLA Citation
Lei, Kefeng, et al. “Mutant allele quantification reveals a genetic basis for TP53 mutation-driven castration resistance in prostate cancer cells..” Sci Rep, vol. 8, no. 1, Aug. 2018. Pubmed, doi:10.1038/s41598-018-30062-z.
URI
https://scholars.duke.edu/individual/pub1344191
PMID
30131529
Source
pubmed
Published In
Scientific Reports
Volume
8
Published Date
Start Page
12507
DOI
10.1038/s41598-018-30062-z

Adaptive Evolution of the GDH2 Allosteric Domain Promotes Gliomagenesis by Resolving IDH1R132H-Induced Metabolic Liabilities.

Hotspot mutations in the isocitrate dehydrogenase 1 (IDH1) gene occur in a number of human cancers and confer a neomorphic enzyme activity that catalyzes the conversion of α-ketoglutarate (αKG) to the oncometabolite D-(2)-hydroxyglutarate (D2HG). In malignant gliomas, IDH1R132H expression induces widespread metabolic reprogramming, possibly requiring compensatory mechanisms to sustain the normal biosynthetic requirements of actively proliferating tumor cells. We used genetically engineered mouse models of glioma and quantitative metabolomics to investigate IDH1R132H-dependent metabolic reprogramming and its potential to induce biosynthetic liabilities that can be exploited for glioma therapy. In gliomagenic neural progenitor cells, IDH1R132H expression increased the abundance of dipeptide metabolites, depleted key tricarboxylic acid cycle metabolites, and slowed progression of murine gliomas. Notably, expression of glutamate dehydrogenase GDH2, a hominoid-specific enzyme with relatively restricted expression to the brain, was critically involved in compensating for IDH1R132H-induced metabolic alterations and promoting IDH1R132H glioma growth. Indeed, we found that recently evolved amino acid substitutions in the GDH2 allosteric domain conferred its nonredundant, glioma-promoting properties in the presence of IDH1 mutation. Our results indicate that among the unique roles for GDH2 in the human forebrain is its ability to limit IDH1R132H-mediated metabolic liabilities, thus promoting glioma growth in this context. Results from this study raise the possibility that GDH2-specific inhibition may be a viable therapeutic strategy for gliomas with IDH mutations.Significance: These findings show that the homonid-specific brain enzyme GDH2 may be essential to mitigate metabolic liabilities created by IDH1 mutations in glioma, with possible implications to leverage its therapeutic management by IDH1 inhibitors. Cancer Res; 78(1); 36-50. ©2017 AACR.
Authors
Waitkus, MS; Pirozzi, CJ; Moure, CJ; Diplas, BH; Hansen, LJ; Carpenter, AB; Yang, R; Wang, Z; Ingram, BO; Karoly, ED; Mohney, RP; Spasojevic, I; McLendon, RE; Friedman, HS; He, Y; Bigner, DD; Yan, H
MLA Citation
Waitkus, Matthew S., et al. “Adaptive Evolution of the GDH2 Allosteric Domain Promotes Gliomagenesis by Resolving IDH1R132H-Induced Metabolic Liabilities..” Cancer Res, vol. 78, no. 1, Jan. 2018, pp. 36–50. Pubmed, doi:10.1158/0008-5472.CAN-17-1352.
URI
https://scholars.duke.edu/individual/pub1284283
PMID
29097607
Source
pubmed
Published In
Cancer Res
Volume
78
Published Date
Start Page
36
End Page
50
DOI
10.1158/0008-5472.CAN-17-1352

Immunotoxin Therapy for Lung Cancer.

Authors
Xie, L-Y; Piao, H-L; Fan, M; Zhang, Z; Wang, C; Bigner, DD; Bao, X-H
MLA Citation
Xie, Li-Yi, et al. “Immunotoxin Therapy for Lung Cancer..” Chin Med J (Engl), vol. 130, no. 5, Mar. 2017, pp. 607–12. Pubmed, doi:10.4103/0366-6999.200540.
URI
https://scholars.duke.edu/individual/pub1226022
PMID
28229994
Source
pubmed
Published In
Chin Med J (Engl)
Volume
130
Published Date
Start Page
607
End Page
612
DOI
10.4103/0366-6999.200540

Phase I trial of combination of antitumor immunotherapy targeted against cytomegalovirus (CMV) plus regulatory T-cell inhibition in patients with newly-diagnosed glioblastoma multiforme (GBM).

Authors
Vlahovic, G; Archer, GE; Reap, E; Desjardins, A; Peters, KB; Randazzo, D; Healy, P; Herndon, JE; Friedman, AH; Friedman, HS; Bigner, DD; Sampson, JH
MLA Citation
Vlahovic, Gordana, et al. “Phase I trial of combination of antitumor immunotherapy targeted against cytomegalovirus (CMV) plus regulatory T-cell inhibition in patients with newly-diagnosed glioblastoma multiforme (GBM)..” Journal of Clinical Oncology, vol. 34, no. 15_suppl, American Society of Clinical Oncology (ASCO), 2016, pp. e13518–e13518. Crossref, doi:10.1200/jco.2016.34.15_suppl.e13518.
URI
https://scholars.duke.edu/individual/pub1266936
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
34
Published Date
Start Page
e13518
End Page
e13518
DOI
10.1200/jco.2016.34.15_suppl.e13518